Bromocyclization of Alkynyl Guanidine: A New Approach to the Synthesis of Cyclic Guanidines of Saxitoxin

Abstract

Bromocyclization of propargyl and homopropargyl guanidines possessing homopropargyl alcohol provides five- and six-membered cyclic guanidines with spiro-hemiaminal, respectively, a candidate of precursors for saxitoxin.

Key words

saxitoxin - cyclic guanidine - alkynyl guanidine - bromocyclization - spiro-hemiaminal

References and Notes

• 1 Berlinck RGS. Burtoloso ACB. Trindade-Silva AE. Romminger S. Morais RP. Bandeira K. Mizuno CM. Nat. Prod. Rep.  2010,  27:  1871 ; and references cited therein
• 2 Llewellyn LE. Nat. Prod. Rep.  2006,  23:  200 
• 3 For synthetic studies on tetrodotoxin from this laboratory, see: Urabe D. Nishikawa T. Isobe M. Chem. Asian J.  2006,  1:  125 ; and references cited therein
• 4a Tanino H. Nakata T. Kaneko T. Kishi Y. J. Am. Chem. Soc.  1977,  99:  2818 
• 4b Kishi Y. Heterocycles  1980,  14:  1477 
• 4c Hong CY. Kishi Y. J. Am. Chem. Soc.  1992,  114:  7001 
• 5a Jacobi PA. Martinelli MJ. Polanc S. J. Am. Chem. Soc.  1984,  106:  5594 
• 5b Martinelli MJ. Brownstein AD. Jacobi PA. Polanc S. Croat. Chem. Acta  1986,  59:  267 
• 5c Jacobi PA. In Strategies and Tactics in Organic Synthesis   Vol. 2:  Lindberg T. Academic Press; New York: 1989.  p.191-219  
• 6a Fleming JJ. Du Bois J. J. Am. Chem. Soc.  2006,  128:  3926 
• 6b Fleming JJ. McReynolds MD. Du Bois J.
  J. Am. Chem. Soc.  2007,  129:  9964 
• 6c Mulcahy JV. Du Bois J. J. Am. Chem. Soc.  2008,  130:  12630 
• 6d Andresen BM. Du Bois J. J. Am. Chem. Soc.  2009,  131:  12524 
• 7a Iwamoto O. Koshino H. Hashizume D. Nagasawa K. Angew. Chem. Int. Ed.  2007,  46:  8625 
• 7b Iwamoto O. Shinohara R. Nagasawa K. Chem. Asian J.  2009,  4:  277 
• 7c Iwamoto O. Nagasawa K. Org. Lett.  2010,  12:  2150 
• 8 Mao H. Fieber LA. Gawley RE. ACS Med. Chem. Lett.  2010,  1:  135 
• 9a Baldwin JE. J. Chem. Soc., Chem. Commun.  1976,  734 
• 9b Baldwin JE. J. Chem. Soc., Chem. Commun.  1976,  736 
• 10 The iodocyclization of alkynyl imidazolinone was reported. See: Noguchi M. Okada H. Watanabe M. Okuda K. Nakamura O. Tetrahedron  1996,  52:  6581 
• During preparation of this manuscript, transition-metal-catalyzed cyclizations of alkynyl guanidines were reported:
• 11a Gainer MJ. Bennett NR. Takahashi Y. Looper RE. Angew. Chem. Int. Ed.  2011,  50:  684 
• 11b Ermolat’ev DS. Bariwal JB. Steenackers HPL. De Keersmaecker SCJ. Van der Eycken EV. Angew. Chem. Int. Ed.  2010,  49:  9465 
• 11c Perl NR. Ide ND. Prajapati S. Perfect HH. Durón SG. Gin DY. J. Am. Chem. Soc.  2010,  132:  1802 
• 11d Giles RL. Sullivan JD. Steiner AM. Looper RE. Angew. Chem. Int. Ed.  2009,  48:  3116 
• 12 Garner P. Park JM. Org. Synth., Coll. Vol. IX  1998,  300 
• 13 Fujisawa T. Nagai M. Koike Y. Shimizu M. J. Org. Chem.  1994,  59:  5865 
• 14 Kan T. Fukuyama T. Chem. Commun.  2004,  353 
• 15 Yoshida Y. Sakakura Y. Aso N. Okada S. Tanabe Y. Tetrahedron  1999,  55:  2183 
• 18a Disadee W. Ishikawa T. Kawahata M. Yamaguchi K. J. Org. Chem.  2006,  71:  6600 
• 18b White J. Baker DC. Synthesis  1990,  151 
• 18c Fromm von E. Arbeiten N. Barrenscheen H. Frieder J. Pirk L. Kapeller R. Justus Liebigs Ann. Chem.  1925,  442:  130 
• Isolation and structure reassignment of crambescin B:
• 19a Berlinck RGS. Braekman JC. Daloze D. Hallenga K. Ottinger R. Riccio IBR. Tetrahedron Lett.  1990,  31:  6531 
• 19b Snider BB. Shi Z. J. Org. Chem.  1993,  58:  3828 

16

In fact, when 11a was exposed to NBS in CH₂Cl₂, aminoimidazole 12a was obtained.

17

The structure of 14 was supported by extensive NMR analysis of the di-Boc analogue of 14 (as a single product) prepared from 6 with di-Boc-methylisothiourea in a similar manner. See Supporting Information.